This invention relates to new antibiotics, new intermediate products useful in the preparation of these antibiotics, and processes for the preparation of these compounds. More particularly, it is concerned with new 6-aminopenicillanic acid derivatives having a methoxy or thioalkyl substituent at position 6, and with new intermediates and processes for their production.
The discovery of penicillin, which was found to be such an important and effective antibiotic, stimulated great interest in this field. Subsequently, various other antibiotics such as streptomycin, the tetracyclines, novobiocin, and the like were found which greatly increased the doctors' armamentarium for treating infections due to a variety of pathogens. Unfortunately, the use of these antibiotics gave rise to strains of pathogens resistant to these known antibiotics. In addition, the known antibiotics suffer from the disadvantage that they are only effective against certain types of microorganisms and are not effective against a broad range of pathogens. Accordingly, the search for other antibiotics has continued.
It is an object of this invention to provide new penicillins having antibiotic activity. A further object is to provide processes for the preparation of these new antibiotics. Another object is to provide new intermediates useful in preparing these new penicillins. Other objects will be apparent from the detailed description of this invention hereinafter provided.
The new penicillins of the present invention are compounds wherein the penam nucleus, namely a thioazolidine ring with a fused .beta.-lactam, contains a methoxy or thiomethyl substituent at the 6-position. Thus, these new penicillins which can be represented by the structural formula: ##STR1## wherein R' represents an acyl group and R.sub.1 is methoxy or thioloweralkyl or 1-6 carbon atoms; n is 0 or 1; and derivatives thereof, such as esters, amides, and salts, are valuable new antibiotic substances. Compounds wherein R.sub.1 is thiolower alkyl are also valuable as intermediates to make the 6-methoxy compounds. Compounds where n=1 are also valuable intermediates to make novel cephalosporins.
The acyl radical represented by R' can be a substituted or unsubstituted aliphatic acyl, aromatic acyl, heterocyclic acyl, araliphatic acyl or heterocyclylaliphatic acyl radical derived from a carboxylic acid or a carbothioic acid such as the acyl radicals of the known cephalosporins and penicillins. These acyl radicals can be represented by the general formula: ##STR2## where R.sub.2 is a radical of the group defined below, m and n represent 0-4 and R.sub.3 represents R" or ZR", which are defined below.
One group of acyl radicals can be represented by the acyl group general formula: ##STR3## wherein R" represents a substituted or unsubstituted straight or branched chain alkyl, alkenyl or alkynyl; aryl; aralkyl; cycloalkyl; heteroaryl or heteroaralkyl. dibromomethyl, 1-(3-methylimidazolyl)methyl, 2- or 3-(5-carboxymethylthienyl)methyl, 2- or 3-(5-carbamoylthienyl)-methyl, 2- or 3-(5-methylthienyl)methyl, 2- or 3-(5-methoxythienyl)methyl, 2- or 3-(5-chlorothienyl)methyl, 2- or 3-(5-sulfothienyl)methyl, 2- or 3-(5-carboxythienyl)methyl, 3-(1,2,5-thiadiazolyl)methyl, 3-(4-methoxy-1,2,5-thiadiazolyl)methyl, 2-furylmethyl, 2-(5-nitrofuryl)methyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, and 1-tetrazolylmethyl.
The acyl group can also be a radical of the formula: ##STR4## wherein n is an integer of 0-4, Z is oxygen or sulfur, and R" is defined as above. Representative members of the substituent EQU --(CH.sub.2).sub.n ZR"
that might be mentioned are allylthiomethyl, phenylthiomethyl, butylmercaptomethyl, .alpha.-chlorocrotylmercaptomethyl, phenoxymethyl, .alpha.-phenoxyethyl, .alpha.-phenoxybutyl, phenoxybenzyl, diphenoxymethyl, dimethylmethoxymethyl, dimethylbutoxymethyl, dimethylphenoxymethyl, 4-guanidinophenoxymethyl, 4-pyridylthiomethyl, p-(carboxymethyl)phenoxymethyl, p-(carboxymethyl)phenylthiomethyl, 2-thiazolylthiomethyl, p-(sulfo)phenoxymethyl, p-(sulfo)phenylthiomethyl, p-(carboxy)phenoxymethyl, p-(carboxy)phenylthiomethyl, p-(carboxymethyl)phenoxymethyl, p-(carboxymethyl)phenylthiomethyl, 2-pyrimidinylthiomethyl, phenethylthiomethyl, 1-(5,6,7,8-tetrahydronaphthyl)oxomethyl, 6,8-bis(methylthio)octanoyl.
Alternatively, the acyl group can be a radical of the formula: ##STR5## These groups can be unsubstituted or can be substituted by radicals such as alkyl, alkoxy, halo, cyano, carboxy, sulfoamino, carbamoyl, sulfonyl, azido, amino, substituted amino, haloalkyl, carboxyalkyl, carbamoylalkyl, N-substituted carbamoylalkyl, guanidino, N-substituted guanidino, guanidinoalkyl, and the like. Representative examples of such acyl groups that might be mentioned are those wherein R" is benzyl, p-hydroxybenzyl, 4-amino-4-carboxybutyl, methyl, cyanomethyl, 2-pentenyl, n-amyl, n-heptyl, ethyl, 3- or 4-nitrobenzyl, phenethyl, .beta.,.beta.-diphenylethyl, methyldiphenylmethyl, triphenylmethyl, 2-methoxyphenyl, 2,6-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 3,5-dimethyl-4-isoxazolyl, 3-butyl-5-methyl-4-isoxazolyl, 5-methyl-3-phenyl-4-isoxazolyl, 3-(2-chlorophenyl)-5-methyl-4-isoxazolyl, 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolyl, D-4-amino-4-carboxybutyl, D-4-N-benzoylamino-4-carboxy-n-butyl, p-aminobenzyl, o-aminobenzyl, m-aminobenzyl, (3-pyridyl)methyl, 2-ethoxy-1-naphthyl, 3-carboxy-2-quinoxalinyl, 3-(2,6-dichlorophenyl)-5-(2-furyl)-4-isoxazolyl, 3-phenyl-4-isoxazolyl, 5-methyl-3-(4-guanidinophenyl)-4-isoxazolyl, 4-guanidinomethylphenyl, 4-guanidinomethylbenzyl, 4-guanidinobenzyl, 4-guanidinophenyl, 2,6-dimethoxy-4-guanidinophenyl, o-sulfobenzyl, p-carboxymethylbenzyl, p-carbamoylmethylbenzyl, m-fluorobenzyl, m-bromobenzyl, p-chlorobenzyl, p-methoxybenzyl, 1-naphthylmethyl, 3-isothiazolylmethyl, 4-isothiazolylmethyl, 5-isothiazolylmethyl, 4-pyridylmethyl, 5-isoxazolylmethyl, 4-methoxy-5-isoxazolylmethyl, 4-methyl-5-isoxazolylmethyl, 1-imidazolylmethyl, 2-benzofuranylmethyl, 2-indolylmethyl, 2-phenylvinyl, 2-phenylethynyl, 2-(5-nitrofuranyl)vinyl, phenyl, o-methoxyphenyl, o-chlorophenyl, o-phenylphenyl, p-aminomethylbenzyl, 1-(5-cyanotriazolyl)methyl, difluoromethyl, dichloromethyl, wherein R" is defined as above and R'" is amino, hydroxy, azido, carbamoyl, guanidino, acyloxy, halo, sulfamino, tetrazolyl, sulfo, carboxy or carbalkoxy. Representative members of the substituent that might be mentioned are .alpha.-aminobenzyl, .alpha.-amino-2-thienylmethyl, .alpha.-methylaminobenzyl, .alpha.-amino-.gamma.-methylmercaptopropyl, .alpha.-amino-3 or 4-chlorobenzyl, .alpha.-amino-3 or 4-hydroxybenzyl, .alpha.-amino-2,4-dichlorobenzyl, .alpha.-amino-3,4-dichlorobenzyl, D(-)-.alpha.-hydroxybenzyl, .alpha.-carboxybenzyl, .alpha.-amino-3-thienylmethyl, D(-)-.alpha.-amino-3-chloro-4-hydroxybenzyl, D(-)-.alpha.-amino-3-thienylm ethyl, 1-aminocyclohexyl, .alpha.-(5-tetrazolyl)-benzyl, .alpha.-sulfaminobenzyl, .alpha.-sulfamino-3-thienylmethyl, .alpha.-(N-methylsulfamino)benzyl, D(-)-.alpha.-guanidino-2-thienylmethyl, D(-)-.alpha.-guanidinobenzyl, .alpha.-guanylureidobenzyl, .alpha.-hydroxybenzyl, .alpha.-azidobenzyl, .alpha.-fluorobenzyl, 4-(5-methoxy-1,3-oxadiazole)-aminomethyl, 4-(5-methoxy-1,3-oxadiazole)-hydroxymethyl, 4-(5-methoxy-1,3-oxadiazole)-carboxymethyl, 4-(5-methoxy-1,3-sulfadiazole)-aminomethyl, 4-(5-methoxy-1,3-sulfadiazole)-hydroxymethyl, 4-(5-methoxy-1,3-sulfadiazole)-carboxymethyl, 2-(5-chlorothienyl)-aminomethyl, 2-(5-chlorothienyl)-hydroxymethyl, 2-(5-chlorothienyl)-carboxymethyl, 3-(1,2-thiazole)-aminomethyl, 3-(1,2-thiazole)-hydroxymethyl, 3-(1,2-thiazole)-carboxymethyl, 2-(1,4-thiazolyl)-aminomethyl, 2-(1,4-thiazolyl)-hydroxymethyl, 2-(1,4-thiazolyl)-carboxymethyl, 2-benzothienylaminomethyl, 2-benzothienylhydroxymethyl, 2-benzothienylcarboxymethyl, 2-azidooctyl-3-phenyl-3-azidomethyl, .alpha.-phosphonobenzyl and .alpha.-sulfobenzyl.
Alternatively, the group ##STR6## can be a sulfonamido group such as phenylsulfonamido, ethylsulfonamido, benzylsulfonamido, 2,5-dimethylsulfonamido, 4-chlorosulfonamido, 4-chlorophenylsulfonamido, 4-methoxysulfonamido, and the like.
The acyl substituents of the general formula: ##STR7## wherein R.sub.10 and R.sub.11 are as defined below represent a preferred group of substituents because of their generally enhanced antibiotic activity. R.sub.10 is hydrogen, amino, guanidino, hydroxy, carboxy, tetrazolyl, sulfo or sulfamino. R.sub.11 is phenyl, substituted phenyl, a monocyclic 5- or 6-membered heterocyclic ring containing one to four hetero atoms selected from oxygen, sulfur, nitrogen or phenylthio.
Examples of these preferred acyl substituents that might be mentioned are phenylacetyl, 4-carboxylmethylphenylacetyl, 2-carboxyphenylacetyl, 2-methyl-2-phenoxyacetyl, 3-furylacetyl, 2-thienylacetyl, phenoxyacetyl, 3-thienylacetyl, 3-isothiazolylacetyl, 4-isothiazolylacetyl, phenylthioacetyl, 4-pyridylthioacetyl, tetrazolylacetyl, .alpha.-fluorophenylacetyl, D-phenylglycyl, 3-hydroxy-D-phenylglycyl, 2-thienylglycyl, 3-thienylglycyl, phenylmalonyl, 3-thienylmalonyl, .alpha.-sulfaminophenylacetyl, .alpha.-hydroxyphenylacetyl, .alpha.-tetrazolylphenylacetyl and .alpha.-sulfophenylacetyl.
The new penicillins of this invention can be used as antibiotics in the form of derivatives such as metal salts, for example, sodium potassium or ammonium salts, amine salts, for example, procaine, or N,N'-dibenzylethylenediamine salts, or amides and substituted amides, as is well known in this art.
Alternatively, labile esters which are metabolized readily such as groups of the formula --CH.sub.2 OCO(CH.sub.2).sub.n --A where n is an integer from 0 to 5 and A is an unsubstituted or substituted aliphatic, alicyclic, aromatic or heterocyclic radical represent preferred species of ester derivatives suitable for use in antibiotic therapy. Other esters of the new penicillins such as lower alkyl, aralkyl, aryl, silyl, halo lower alkyl, or stannyl esters are suitable for use as intermediates in preparing the free acid and salts thereof in accordance with methods known in this art.
In accordance with the present invention, it is now found that the new penicillins of this invention can be prepared by processes which can be depicted as follows: ##STR8##
In the foregoing flowsheet the starting compound is a derivative of 6-diazopenicillanic acid wherein the carboxy group is preferably blocked, for example, by forming a suitable ester. These 6-diazopenicillanic acid esters are readily prepared by esterifying 6-aminopenicillanic acid and reacting the ester with nitrite. Thus, the 6-aminopenicillanic acid can be esterified in accordance with methods well known in this art to obtain, for example, the esters wherein R.sub.8 represents an alkyl group such as methyl, t-butyl, and the like, a haloalkyl group such as trichloroethyl, an alkenyl group such as allyl, an alkynyl group such as propargyl, an aralkyl group such as benzyl, p-methoxybenzyl, o-nitrobenzyl, an organometallic group, for example, a silyl group such as trimethylsilyl, or a stannyl group such as tributyltin or phenacyl. The 6-diazopenicillanic acid ester (II) is converted by reaction with a compound of the formula: XY, to form intermediate product (III) wherein X represents halogen and Y is a nitrogenous substituent or R.sub.1. Similarly a mixture of compounds one of which is the source of a positive halogen is an N-haloamide such as N-bromosuccinimide, N-bromophthalimide or N-bromoacetamide or halo and the other of which is a source of Y. Intermediate compound (III) is then converted to compound (IV) in which Z' represents a nitrogenous group which is readily convertible to amino or acylamino. Compound (IV) is then converted to the desired penicillin ester which can be reacted to obtain the corresponding penicillin acid or a salt thereof. The processes for carrying out the various steps of the foregoing flowsheet will be more readily understood from the detailed descriptions of methods which can be used to carry out these processes.
Thus, in accordance with one specific embodiment of this invention, the new penicillins are obtained by the following processes: ##STR9##
In the one variation of the above process the diazopenicillanic acid ester (II) is reacted with a halo azide from the group consisting of bromine, chlorine, or iodine azide, preferably in the presence of a tertiary amine azide, to produce the intermediate 6-halo-6-azidopenicillanic acid ester (V) which on reaction with a suitable nucleophilic reagent such as methanol or loweralkyl sulfenyl bromide, is converted to the desired 6-R.sub.1 -6-azidopenicillanic acid ester (VI). Alternatively, II is treated with an alcohol or thiol hyophalite to give Va which is treated with azide anion to give VI. This intermediate product is reduced and acylated in one step to form the substituted penicillanate ester (IX) which can then be cleaved to remove the blocking group and obtain the penicillanic acid or a salt thereof (X). Alternatively, as shown in the flowsheet, the 6-R.sub.1 -6-azidopenicillanic acid ester (VI) is reduced to the 6-R.sub.1 -6-aminopenicillanic acid ester (VII) which can be acylated to produce the 6-R.sub.1 -6-acylaminopenicillanic acid ester (IX), or the ester group of compound (VII) can be cleaved to obtain the free acid (VIII) which can be acylated to form the desired substituted penicillanic acid or a salt thereof. The step of cleaving the blocking group is readily effected in accordance with methods known in this art. For example, an aralkyl group such as the benzyl ester is removed by reduction, a silyl ester can be removed by hydrolysis to form the free acid or a salt thereof. In this process other esters which are readily cleaved to form the free acid as trichloroethyl, p-methoxybenzyl, o-nitrobenzyl, phenacyl and t-butyl and the like can be used.
The step of producing the halo azide intermediate is carried out by reacting the diazo compound with a halo azide at a temperature between about 0 .degree. and -50.degree. C. for sufficient time to complete the formation of the desired compound. The reaction is preferably carried out in a suitable organic solvent medium which is inert to the reactants. Various solvents which do not contain an active hydrogen such as methylene chloride, chloroform, benzene, toluene, ether and the like, or mixtures thereof provide suitable mediums for carrying out the reaction. Generally, it is preferred to effect the reaction in the presence of a second azide such as lithium azide or a tertiary ammonium azide, for example triethylammonium azide, since under these conditions the formation of the undesired 6-dibromo compound is avoided. The halo azide is used in an amount in slight excess of stoichemetric requirements. The amount of second azide is not critical and it is generally desirable to use an excess in order to obtain maximum yields of the desired halo azido compound under optimum conditions. After completion of the formation of the halo azide the product is recovered and can be purified further, for example by chromatography, in accordance with processes well known in this art.
The next step of the process, comprising the replacement of the halo substituent, is effected by reacting the halo azide with a substance capable of furnishing the methoxy or thiomethyl group to replace the halo. This reaction can be carried out in the presence of a suitable nonreactant solvent such as methylene chloride, chloroform, benzene, toluene, ether, petroleum ether and the like, or preferably using the nucleophile itself, e.g., methanol, as solvent. The reaction is preferably carried out in the presence of a suitable acid scavenger such as an alkali or preferably a tertiary amine such an pyridine or a silver salt such Ag.sub.2 O, AgBF.sub.4, AgOSO.sub.2 CF.sub.3.
In the next step of the above-described process the 6-azido-6-R.sub.1 compound is then reduced to afford the corresponding 6-amino-6R.sub.1 compound. Various methods of carrying out this reduction can be employed, but it is generally preferred to carry out the reduction of the azido to the amino group by catalytic hydrogenation employing a nobel metal catalyst such as platinum, palladium or oxides thereof. These processes are carried out in accordance with procedures well known in this art. Alternatively, the reduction can be effected in the presence of a suitable acylating agent to produce the desired 6-acylamido-6R.sub.1 compound. The 6-amino compound can be reacted with suitable acylating agents using procedures well known in this art to obtain the desired 6-acylamido compounds.
The sulfoxide form of the penicillin (n=1) is prepared by oxidizing a penicillin using oxidizing agents known in the art, or by oxidizing the 6-amino-6-R.sub.1 -penicillin intermediates and then acylating.